Sleep is pervasive, universal, irresistible, tightly regulated, and its loss impairs performance and cognition. Sleep is thought to perform essential restorative functions for the brain, and increasing evidence suggests that sleep may ultimately reflect a local need for homeostasis that is triggered by the cellular consequences of wake, primarily related to the costs of synaptic plasticity associated with learning. This evidence is consistent with the hypothesis that sleep and wake may occur, be regulated, and perform their functions at the level of individual neurons. Recently, using multi-array recordings in freely moving rats, we obtained direct evidence that sleep can occur locally within a group of cortical neurons, while the rest of the brain remains awake, and that such local sleep increases with the duration of wake. If so, does local sleep occur in different species, and what are the underlying mechanisms? Are they similar to those governing the regulation of sleep at the systems level? And do they reflect cellular needs for restoration triggered by the progressive accumulation of plastic changes due to learning in wake (neuronal tiredness) or merely by intense activity (fatigue)? Moreover, are there cellular/ultrastructural signatures of the cost o wake plasticity for brain cells and, conversely, that sleep has occurred and restored homeostasis? Finally, does the occurrence of local sleep during wake lead to performance impairments, which could explain the performance/cognitive deficits observed in sleep-restricted humans and in some neuropsychiatric disorders? These are fascinating and long-standing questions, and it is finally becoming possible to address them directly by taking advantage of several technological breakthroughs that permit single cell analysis and causal manipulations, including multi-array recordings, high-density (hd) EEG, in vivo calcium imaging, thermo/opto/pharmacogenetics, and serial block- face scanning electron microscopy (SBF-SEM). This proposal includes three highly integrated and complementary projects employing flies (Project I), mice (Project II), and humans (Project III) to address three related questions: . Does local sleep occur in different species, and is it triggered by mechanisms similar to those that trigger sleep proper, or merely by fatigue? 2. What are the cellular/ultrastructural signature of wake plasticity and, conversely, of the restorative functions of sleep? 3. What are the behavioral/cognitive consequences of local sleep in an awake brain?